Angiotensin-1-receptor antagonists

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof are described: AA1-Arg-Val-AA4-AA5-His-Pro-AA8-OH  (I), in which AA1, AA4, AA5, and AA8 are defined in the specification. The compounds of formula (I) can be used to treat hypertension (e.g., hypertension induced by pregnancy), preeclampsia, or a renal disease induced by pregnancy.

What is claimed is: 
     
       1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
   AA1-Arg-Val-AA4-AA5-His-Pro-AA8-OH  (I),
 
 
       wherein
 AA1 is an amino acid residue selected from the group consisting of sarcosine and ((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)glycine; 
 AA4 is an amino acid residue selected from the group consisting of tyrosine or meta-tyrosine, each of which is optionally substituted with at least one substituent selected from the group consisting of halo and hydroxyl; 
 AA5 is an amino acid residue selected from the group consisting of valine, leucine, isoleucine, glycine, alanine, phenylalanine, threonine, lysine, and tyrosine, each of which is optionally substituted with at least one substituent selected from the group consisting of C 1-6  alkyl, C 4-6  cycloalkyl, NH 2 , aryl, and heteroaryl; and 
 AA8 is a D-amino acid residue selected from the group consisting of D-1-naphthylalanine, D-(3-benzothienyl)alanine, and D-phenylalanine substituted with at least one substituent selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 4-6  cycloalkyl, halo, CN, aryl, and heteroaryl, in which one said substituent is at the 2-position on the phenyl ring of the D-phenylalanine; 
 wherein each of Arg, Val, AA4, AA5, His, and Pro in formula (I) is an L-amino acid residue. 
 
     
     
       2. The compound of  claim 1 , wherein AA4 is tyrosine optionally substituted with at least one substituent, in which the at least one substituent is at the 3-position on the phenyl ring of the tyrosine. 
     
     
       3. The compound of  claim 2 , wherein AA4 is tyrosine, meta-tyrosine, 3-hydroxytyrosine, or 3-chlorotyrosine. 
     
     
       4. The compound of  claim 1 , wherein AA5 is an amino acid residue selected from the group consisting of valine, leucine, isoleucine, glycine, alanine, phenylalanine, threonine, lysine, and tyrosine, each of which is optionally substituted with at least one substituent selected from the group consisting of CH 3 , cyclobutyl, cyclopentyl, cyclohexyl, NH 2 , thienyl, and thiazolyl. 
     
     
       5. The compound of  claim 4 , wherein AA5 is valine, isoleucine, cyclobutylglycine, cyclopentylglycine, cyclohexylglycine, cyclohexylalanine, leucine, o-methyl threonine, lysine, phenylalanine, tyrosine, 4-aminophenylalanine, 3-thienylalanine, 2-thienylalanine, or 4-thiazolylalanine. 
     
     
       6. The compound of  claim 5 , wherein AA5 is valine, isoleucine, cyclopentylglycine, cyclohexylglycine, or O-methyl threonine. 
     
     
       7. The compound of  claim 1 , wherein AA8 is an amino acid residue selected from the group consisting of D-1-naphthylalanine, D-(3-benzothienyl)alanine, and D-phenylalanine substituted with at least one substituent selected from the group consisting of CH 3 , CF 3 , Cl, Br, CN, and phenyl, in which at least one said substituent is at the 2-position on the phenyl ring of the D-phenylalanine. 
     
     
       8. The compound of  claim 1 , wherein AA8 is D-1-naphthylalanine, D-(3-benzothienyl)alanine, D-2-chlorophenylalanine, D-2-bromophenylalanine, D-2-methylphenylalanine, D-2-trifluoromethylphenylalanine, D-2-cyanophenylalanine, D-2-phenylphenylalanine, D-2,4-dichlorophenylalanine, or D-2,6-dimethylphenylalanine. 
     
     
       9. The compound of  claim 1 , wherein AA1 is sarcosine. 
     
     
       10. The compound of  claim 9 , wherein AA4 is tyrosine, meta-tyrosine, 3-hydroxytyrosine, or 3-chlorotyrosine. 
     
     
       11. The compound of  claim 10 , wherein AA5 is valine, isoleucine, lysine, tyrosine, 4-aminophenylalanine, cyclohexylalanine, cyclopentylglycine, cyclohexylglycine, phenylalanine, O-methyl threonine, 3-thienylalanine, 2-thienylalanine, or 4-thiazolylalanine. 
     
     
       12. The compound of  claim 11 , wherein AA8 is D-1-naphthylalanine, D-(3-benzothienyl)alanine, D-2-chlorophenylalanine, D-2-bromophenylalanine, D-2-methylphenylalanine, D-2-trifluoromethylphenylalanine, D-2-cyanophenylalanine, D-2-phenylphenylalanine, D-2,4-dichlorophenylalanine, or D-2,6-dimethylphenylalanine. 
     
     
       13. The compound of  claim 1 , wherein AA1 is ((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)glycine. 
     
     
       14. The compound of  claim 13 , wherein AA4 is tyrosine. 
     
     
       15. The compound of  claim 14 , wherein AA5 is valine or cyclohexylglycine. 
     
     
       16. The compound of  claim 15 , wherein AA8 is D-1-naphthylalanine, D-(3-benzothienyl)alanine, D-2-chlorophenylalanine, D-2-methylphenylalanine, or D-2-phenylphenylalanine. 
     
     
       17. The compound of  claim 1 , wherein the compound is
 (1) Sar-Arg-Val-Tyr-Val-His-Pro-(D-1Nal)—OH; 
 (2) Sar-Arg-Val-Tyr-Lys-His-Pro-(D-1Nal)—OH; 
 (3) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-CF 3 ))—OH; 
 (4) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Cl))—OH; 
 (5) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-CN))—OH; 
 (6) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Ph))—OH; 
 (7) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2,4-diCl))—OH; 
 (8) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2,6-diMe))—OH; 
 (9) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH; 
 (10) Sar-Arg-Val-Tyr-Val-His-Pro-(D-(3-benzothienyl)alanine)—OH; 
 (11) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Br))—OH; 
 (12) Sar-Arg-Val-Tyr-Tyr-His-Pro-(D-1Nal)—OH; 
 (13) Sar-Arg-Val-Tyr-Aph-His-Pro-(D-1Nal)—OH; 
 (14) Sar-Arg-Val-Tyr-Cha-His-Pro-(D-1Nal)—OH; 
 (15) Sar-Arg-Val-Tyr-Cpg-His-Pro-(D-1Nal)—OH; 
 (16) Sar-Arg-Val-Tyr-Phe-His-Pro-(D-1Nal)—OH; 
 (17) Sar-Arg-Val-Tyr-Thr(Me)-His-Pro-(D-1Nal)—OH; 
 (18) Sar-Arg-Val-Tyr-Cpg-His-Pro-(D-Phe(2-Cl))—OH; 
 (19) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Cl))—OH; 
 (20) Sar-Arg-Val-Tyr-Aph-His-Pro-(D-Phe(2-Cl))—OH; 
 (21) Sar-Arg-Val-Tyr-Thr(Me)-His-Pro-(D-Phe(2-Cl))—OH; 
 (22) Sar-Arg-Val-Tyr-(3-Thi)-His-Pro-(D-Phe(2-Cl))—OH; 
 (23) Sar-Arg-Val-Tyr-(2-Thi)-His-Pro-(D-Phe(2-Cl))—OH; 
 (24) Sar-Arg-Val-Tyr-(A1a(4-Thz))-His-Pro-(D-Phe(2-Cl))—OH; 
 (25) Sar-Arg-Val-Tyr-Ile-His-Pro-(D-Phe(2-Cl))—OH; 
 (26) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-CF 3 ))—OH; 
 (27) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Me))—OH; 
 (28) Sar-Arg-Val-Tyr(3-Cl)-Va1-His-Pro-(D-Phe(2-Cl))—OH; 
 (29) Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Cl))—OH; 
 (30) Sar-Arg-Va1-(m-Tyr)-Va1-His-Pro-(D-Phe(2-Cl))—OH; 
 (31) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Cl))—OH; 
 (32) Sar-Arg-Va1-DOPA-Va1-His-Pro-(D-Phe(2-Cl))—OH; 
 (33) Sar-Arg-Val-Aph-Val-His-Pro-(D-Phe(2-Cl))—OH; 
 (34) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-1Nal)—OH; 
 (35) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-(3-benzothienyl)alanine)—OH; 
 (36) Sar-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Ph))—OH; 
 (37) Glac-Arg-Val-Tyr-Val-His-Pro-(D-1Nal)—OH; 
 (38) Glac-Arg-Val-Tyr-Val-His-Pro-(D-(3-benzothienyl)alanine)—OH; 
 (39) Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Ph))—OH; 
 (40) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-1Nal)—OH; 
 (41) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-(3-benzothienyl)alanine)—OH; 
 (42) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Ph))—OH; 
 (43) Glac-Arg-Val-Tyr-Cpg-His-Pro-(D-Phe(2-Cl))—OH; 
 (44) Glac-Arg-Val-Tyr-Cpg-His-Pro-(D-Phe(2-Me))—OH; 
 (45) Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH; or 
 (46) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Me))—OH. 
 
     
     
       18. The compound of  claim 1 , wherein the compound is:
 (4) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Cl))—OH; 
 (9) Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH; 
 (29) Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Cl))—OH; 
 (31) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Cl))—OH; 
 (45) Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH; or 
 (46) Glac-Arg-Val-Tyr-Chg-His-Pro-(D-Phe(2-Me))—OH. 
 
     
     
       19. The compound of  claim 1 , wherein AA8 is D-phenylalanine substituted at one or two positions with a substituent selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 4-6  clycloalkyl, halo, CN, aryl, an heteroaryl, wherein one said substituent is at the 2-position on the phenyl ring of the D-phenylalanine. 
     
     
       20. The compound of  claim 1 , wherein the compound exhibits angiotensin-1-receptor (AT1R) antagonist activity. 
     
     
       21. The compound of  claim 1 , wherein the compound exhibits reduces AT1R agonist activity as compared to sarilesin. 
     
     
       22. The compound of  claim 18 , wherein the compound is:
 Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Cl))—OH. 
 
     
     
       23. The compound of  claim 18 , wherein the compound is:
 Sar-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH. 
 
     
     
       24. The compound of  claim 18 , wherein the compound is:
 Glac-Arg-Val-Tyr-Val-His-Pro-(D-Phe(2-Me))—OH. 
 
     
     
       25. A pharmaceutical composition, comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       26. A method of treating hypertension, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of  claim 25 . 
     
     
       27. The method of  claim 26 , wherein the hypertension is induced by pregnancy. 
     
     
       28. A method of treating preeclampsia or a renal disease induced by pregnancy, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of  claim 25 .